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Malaria infection: Heparan sulfate says open sesame

Functional Glycomics (13 December 2007) | doi:10.1038/fg.2007.52

Proteolytic cleavage of the Plasmodium sporozoite cell surface circumsporozoite protein (CSP) is triggered by hepatocyte highly sulfated heparan sulfate proteoglycans (HSPGs), initiating a signaling pathway that involves calcium-dependent protein kinase (CDPK)-6 and leads to the switch from sporozoite migration to invasion.

Plasmodium sporozoites (green) are deposited under the skin of the vertebrate host through the bite of an infected female Anopheles mosquito.

After Plasmodium sporozoites are injected into the mammalian host by Anopheles mosquitoes they must traverse through various cell types in order to reach the liver, where they invade hepatocytes and start to replicate in a parasitophorous vacuole. CSP is likely to be involved in hepatocyte invasion as CSP cleavage occurs during invasion, but not during cell traversal. In Cell Host and Microbe, Coppi et al. now elucidate the connection between CSP cleavage, binding of sporozoites to cell surface HSPGs and the switch to the invasive phenotype.

Coppi et al. observed that when sporozoites were added to hepatoma Hepa 1-6 cells line pretreated with the HSPG-sulfation-inhibitor chlorate, they exhibited a dose-dependent increase in migration and dose-dependent decrease in invasion and CSP cleavage. These effects could be reversed by sulfate addition. These findings indicate that the abundance of HSPG sulfation may play a role in the sporozoites' switch from migration to invasion.

Importantly, a change from a low to high HSPG sulfation pattern occurs physiologically when sporozoites travel from the skin, where they are injected, into the blood circulation and then to the liver. Dermal fibroblasts and endothelial cells were shown to have 0.4 – 0.6 sulfates per disaccharide respectively, whereas Hepa 1-6 cells possess 1 sulfate per disaccharide. Interestingly, sporozoites migrate more through dermal fibroblasts and endothelial cells; contact with these cells does not trigger CSP cleavage and invasion into the cell.

Prompted by the observation that sporozoite treatment with kinase inhibitors abated invasion, Coppi et al. uncovered a putative signaling pathway initiated after sporozoite contact with highly-sulfated HSPGs. The authors found that inhibition of CDPKs enhanced sporozoite migration and inhibited cell invasion. More specifically, deletion of the gene encoding CDPK-6 resulted in sporozoites that cleaved CSP inefficiently and invaded hepatocytes poorly but exhibited enhanced migratory activity. These data suggest that CDPK-6 is a major signaling molecule in sporozoite invasion.

Taken together, these results have led to a model of sporozoite invasion in which highly sulfated HSPGs on liver cells trigger CSP cleavage and initiate a signaling pathway involving CDPK-6. The presented study is a big leap in our understanding of the Plasmodium sporozoite life cycle, and another demonstration of the way that HSPG sulfation regulates cell adhesion and signaling.

Mirko von Elstermann

Original paper:

  1. Coppi, A. et al.
    Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells.
    Cell Host Microbe 2, 316–327 (2007).
    doi:10.1016/j.chom.2007.10.002 | Article |